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Caring for the Hospice Patient with Liver Disease

Jennifer Davis, M.D.

December 9, 2011

Objectives

• Common Causes of Liver Disease

• Hospice Criteria for Terminal Diagnosis of Liver Disease

• Treatment of Symptoms of Liver Disease

Common Causes of Liver Disease

• Cirrhosis of Liver without Alcohol 571.5

• Alcoholic Cirrhosis 571.2

• Chronic Hepatitis (HBV, HCV) 571.4

• Hepatocellular Carcinoma 155.0

• Primary Biliary Cirrhosis 571.6

• Autoimmune hepatitis 571.42

• Hepatic Encephalopathy 572.2

Common Causes of Liver Disease

• Hepatorenal Syndrome 572.4

• Hepatopulmonary Syndrome 573.5

• Hemochromatosis 275.03

• Primary Sclerosing Cholangitis 576.1

• Alpha-1-antitrypsin Deficiency 273.4

• Nonalcoholic Fatty Liver Disease 571.8

Cirrhosis

Cirrhosis

• 4.5-9.5% of global population

• Histological development of regenerative nodules surrounded by fibrous bands in response to chronic liver injury that leads to portal hypertension and end stage liver disease

• Usually indolent, asymptomatic and unsuspected until complications of liver disease

• Biopsy is gold standard for diagnosis

Classification of Cirrhosis

• Child-Pugh-Turcotte (CPT): based on

encephalopathy, ascites, bilirubin, albumin,

and PT/INR

• One year survival for class A (100%), B

(80%), C (45%); also predicts complications

Classification of Cirrhosis

• Model for End Stage Liver Disease (MELD):

predicts 3 month survival based on

creatinine, bilirubin, and INR and gives

transplant priority to those more likely to die

without

• Further refinement by giving extra points for

hyponatremia and HCC

Cirrhosis• Signs/Symptoms:

jaundice spider angiomatanodular liver splenomegaly

ascites caput medusae

palmar erythema white nails

Dupuytren’s contracture clubbing

gynecomastia loss of male hair pattern hypogonadism asterixisfoetor hepaticus anorexiafatigue weight loss

muscle atrophy diabetesvariceal bleeding encephalopathy

bacterial infections muscle cramps

hypertrophic osteoarthropathy

spontaneous bacterial peritonitis

Cirrhosis

• Increased: AST/ALT, ALP, GGT, bilirubin,

immunoglobulins

• Decreased: albumin, prothrombin time,

sodium, hemoglobin, platelets, WBCs.

• Consequences: impaired hepatocyte

function, increased intrahepatic resistance,

and hepatocellular carcinoma

• Prognosis and Treatment depend on etiology

Transplant

• Indications: CPT>7 or appropriate MELD score, unresectable liver malignancy, inherited metabolic disorder, no alternative therapy, medical compliance and funding

• Contraindications: HIV, methadone dependence, stage 3 HCC, extrahepatic malignancy, AIDS, cholangiocarcinoma, severe systemic infection, multiorgan failure, advanced cardiopulmonary disease, active substance abuse

Alcoholic Liver Disease

• Signs/Symptoms:

fever hepatosplenomegaly jaundice anorexialiver bruit encephalopathybleeding palmar erythema

gynecomastia caput medusa

clubbing Dupuytren’s contractures

neuropathy testicular atrophy

ascites spider angiomata


• Disproportionate elevation of AST:ALT usually

>2:1, AST and ALT usually <300 IU/L

• Macrocytosis

• Folate and B12 deficiency

• Thrombocytopenia

• Leukocytosis

• Elevated alcohol

• Elevated GGT

• Elevated bilirubin


• Biopsy indicated if enzyme elevations persist for >6 months, other lab evidence of liver failure, uncertain diagnosis, in patients with more than 1 liver disease, prognostication

• Patients with alcoholic cirrhosis without alcohol consumption without transplant have 5 year survival of 60% versus 30% for those who continue to drink alcohol

Hepatitis B Infection

• Signs/Symptoms:

fatigue jaundice

ascites encephalopathy

edema splenomegaly

• Extrahepatic manifestations:

polyarteritis nodosa

glomerular nephropathy and nephritis aplastic anemia

Hepatitis B Infection

• Treatments: antivirals such as entecavir, tenofovir, and, lamivudine, interferon alpha

• 5 year survival:

decompensated liver disease is 14-35% compensated liver disease is 85-90%

• 5 year rate of progression to cirrhosis 12-20%

• HBV may lead to hepatocellular carcinoma without evidence of cirrhosis

Hepatitis C Infection

• Acquired through IV drug use (68%) and STD

(15-20%) and needle sticks (4%)

• Cases acquired through blood transfusion in

1960-1980 now increasing morbidity and

mortality and cost of HCV

• 60-80% develop long term HCV infection and

20-30% of those develop cirrhosis

• HCV accounts for 1/3 of HCC


Factors that increase risk of cirrhosis:

age male

Caucasian HIV

HBV schistosomal

infection alcohol

NASH iron overload


• Signs/Symptoms:

fatigue RUQ pain

nausea anorexia

weakness musculoskeletal pain

weight loss abdominal swelling

dark urine fluid retention

itching

Hepatitis C Infection• Extra-hepatic manifestations of chronic HCV:

mixed cryoglobulinemia

B-cell non-Hodgkin’s lymphoma

glomerulonephritis

seronegative arthritis

keratoconjunctivitis sicca

lichen planus

neuropathycognitive disorders

porphyria cutanea tarda

thyroiditisautoantibodiesdiabetes mellitus


• Most common cause of chronic liver disease

and indication for transplant in U.S.

• 6 genotypes: type 1 most common in U.S. (70-

75%) and most resistant to interferon therapy

• Treatment: Interferon alpha

• Decompensated cirrhosis 5 year survival is 50%

• CDC estimates 8000-13000 deaths per year

from chronic HCV

Hepatocellular Carcinoma

• 5th most common neoplasm in the world and

2nd most common cause of cancer-related

death

• Affects mainly patients with cirrhosis mostly

from HCV, HBV, and/or alcohol abuse

• Signs/Symptoms: pain, early satiety,

jaundice, palpable mass


• Risk factors:

cirrhosis decompensated cirrhosis

HBV HCV

NASH hemochromatosis

aflatoxin co-infection with HCV/HBV/HIV

male increasing age

alcohol positive family history

diabetes contaminated drinking water

Betel nuts abnormal epidermal growth factor

tobacco alpha1antitrysin deficiency

red meat saturated fat

coffee statins


• Paraneoplastic manifestations: erythrocytosis, hypercalcemia, hypoglycemia, diarrhea

• Treatments:

surgical resection

liver transplant

percutaneous ablation with ethanol

radiofrequency ablation

arterial embolization

chemotherapy

palliation


• Yearly screening of cirrhosis patients with imaging in recommended

• Patient with HCV/HCC has 1% 2 year survival

• Mortality is expected to double or triple over next decade.

• Even though new HCV infection is declining, cirrhosis and HCC is increasing.

• With transplant, 1 year survival is 83% and 5 year survival is 70% (UNOS)

Hemochromatosis

• Autosomal recessive iron overload disease

• Inappropriate increase in iron absorption in

the duodenum and upper small intestine

• Deposition of iron in liver, pancreas, heart,

joints, skin, pituitary gland

Hemochromatosis

• Leads to cirrhosis, restrictive

cardiomyopathy, diabetes, arthropathy,

hyperpigmentation, gonadal failure

• Increased risk of cirrhosis and hepatocellular

carcinoma

• Treatment: phlebotomy (goal: ferritin

<50ng/ml), chelation therapy, transplant

Primary Biliary Cirrhosis

• Autoimmune, chronic, cholestatic, granulomatous, progressive destruction of small intrahepatic bile ducts with portal inflammation and fibrosis

• Predominantly affects middle-aged women

• Leads to impaired bile secretion

• Diagnosis 2 out 3: elevated ALP, AMA, and histology showing destruction


• Signs/Symptoms/Extramanifestations:

hepatosplenomegaly xanthelasmas hyperpigmentation itching osteoporosis osteomalacia cirrhosis stigmata hemorrhage cutaneous scleroderma CREST syndrome vitamin D deficiency steatorrhea, hyperbilirubinemia cytopenias Sjogren’s syndrome arthritis cognitive impairment RUQ pain


• Labs: Elevated alkaline phosphatase, GGT, anti-mitochondrial antibodies and IgM, ANA, lipids, later elevated bilirubin

• Treatment:

Ursodeoxycholic acid (bile acid replacement) turns off cycle, 30% respond

Budesonide

plasmapheresis with FFP

ion-exchange resins (questran)

S-adenosyl-L-methionine

transplant

Primary Sclerosing Cholangitis

• Chronic cholestatic liver disease with

inflammation, fibrosis, and strictures of bile

ducts leading to end stage liver disease

• Primarily affects young-middle aged men

• Elevated ALP and nonspecific antibodies

• Cholangiography is gold standard for

diagnosis


• Signs/Symptoms:

pruritus vitamin deficiencies

abdominal pain hyperpigmentation

weight loss steatorrheafever/chills night sweats

fatigue metabolic bone disease

jaundice peristomal varices

gallstones bacterial cholangitis

polyps biliary strictures

IBD cholangiocarcinoma


• Treatment: ursodeoxycholic acid (most

studied, but not proven), endoscopic

dilatation, sphincterotomy, stent, surgical

resection, and transplant

• Survival rate without transplant 10-18 years

• Cholangiocarcinoma occurs in 7-15%

Alpha-1-Antitrypsin Deficiency

• Protein made in liver and transported in

blood to lungs where it protects fragile aveoli

• Common genetic disorder with pulmonary

emphysema and liver cirrhosis and

panniculitis

• 1 in 5000 in U.S. newborns, Scandinavian

• Accelerated by smoking and dust exposure

and increased prevalence of HCC

Alpha-1-Antitrypsin Deficiency

• Signs: Prolonged jaundice after birth, bleeding,

and abnormal liver enzymes

• Cirrhosis/liver failure around age 50

• Emphysema in 30-40s with smoking and 50-

60s if no smoking

• Panniculitis manifests as spontaneous necrosis

• Treatment: IV alpha-1-antitrypsin augmentation

therapy, vaccines, bronchodilators, inhaled

corticosteroids, transplant

Nonalcoholic Fatty Liver Disease

• Most common form of chronic liver disease in Western world (20-35% adults and 5-17% children)

• Dysregulation of lipid metabolism and immune system, genes, environment

• Independent risk factor for CV disease

• Nonalcoholic steatohepatitis 3-5% and cirrhosis 3-5%

• Risk factors: metabolic syndrome, obesity, diabetes II, dyslipidemia

Nonalcoholic Fatty Liver Disease

• NASH also associated with TPN, rapid weight loss, hypothyroidism, abdominal surgery, drugs

• Signs/Symptoms: fatigue, malaise, RUQ pain, elevated enzymes

• Biopsy is gold standard for diagnosis

• Treatment: no proven effective therapy, lifestyle modification including diet and exercise, bariatric surgery, insulin sensitizing drugs

Autoimmune Hepatitis

• Chronic, with circulating autoantibodies and

high serum globulin

• Type 1: ANA and/or ASMA and/or AAA

• Type 2: ALKM-1 and or ALC-1

• Diagnosis: serologic and histologic findings

and exclusion of other liver disease and

scoring system


• Signs/Symptoms:

hepatosplenomegaly jaundice

stigmata of liver disease fatigue

elevated transaminases malaise

anorexia nausea

abdominal pain itching

arthralgias


• Glucocorticoids, Azathioprine, Cyclosporine, Tacrolimus, Methotrexate, Mycophenolate mofetil, Transplant

• Immunosuppressive treatment should be instituted in patients with serum aminotransferases greater than 10-fold the upper limit of normal, at least five-fold the upper limit of normal in conjunction with serum gamma-globulin levels at least two-fold the upper limit of normal, and/or histologic features of bridging necrosis or multilobular necrosis.

Hospice Criteria for Terminal Diagnosis of Liver Disease

Local Coverage Determination (LCD) for Hospice – Liver Disease

1. Patient must have both:

�Prothrombin time prolonged more than 5 seconds over control or INR >1.5 (biosynthetic capacity of clotting factors I, II, V, VII, IX, X, XII, XIII), vitamin K does not correct

�Serum albumin <2.5gm/dl (protein biosynthesis), more common in chronic vs. acute

LDC for Hospice – Liver Disease

2. Patient must have at least one of the following:

�Ascites, refractory or non-compliant

�Spontaneous bacterial peritonitis

�Hepatorenal syndrome, elevated creatinine and BUN with oliguria (<400ml/day), and urine sodium <10mEq/L

�Hepatic encephalopathy, refractory or non-compliant

�Recurrent variceal bleeding, despite intensive therapy

LCD for Hospice – Liver Disease

3. Documentation of these factors supports eligibility:

�Progressive malnutrition

�Muscle wasting with reduced strength and endurance

�Continued active alcoholism (>80gm ethanol/day)

�Hepatocellular carcinoma

�HBsAg positive

�Hepatitis C refractory to interferon treatment

LCD for Hospice - Liver Disease

• Patients awaiting liver transplant who otherwise fit criteria may be certified for the Medicare hospice benefit, but if a donor organ is procured, the patient must be discharged from hospice.

• Notice: No mention of elevated aminotransferases (hepatocellular injury), alkaline phosphatase (cholestasis), or bilirubin (toxin clearance) because these to do not accurately reflect liver function

Symptoms and Complications

• Encephalopathy

• Variceal bleeding

• Ascites

• Spontaneous bacterial peritonitis

• Pruritus

Symptoms and Complications

• Hepatorenal syndrome

• Hepatopulmonary syndrome,

portopulmonary hypertension, and hepatic

hydrothorax

• Cardiovascular effects of liver disease

• Pain

Encephalopathy

• Damaged liver is unable to remove toxins

such as ammonia and manganese from the

blood which then cross the blood-brain

barrier and damage brain cells

• May be exacerbated by TIPS procedure

which redirects blood around the liver

Encephalopathy• Precipitants:

benzodiazepines narcotics

alcohol increased ammonia excess protein intake GI bleedinfection constipation metabolic alkalosis dehydration vomiting diarrhea

hemorrhage diuretics

paracentesis shunt placement spontaneous shunt electrolyte disturbance

portal vein thrombosis hepatic vein thrombosis hepatocellular carcinoma

Encephalopathy

• Signs/Symptoms:

sleep disturbances mood changes,

cognitive deficits psychiatric disorders

coma asterixis

hyperactive DTRs motor disturbances

decerebrate posture

Encephalopathy

• Treatment:

• Treat precipitating factors

• Sugar molecules (lactulose) and antibiotics (neomycin) to reduce GI tract ammonia production

• L-ornithine L-aspartate converts ammonia into glutamine in muscle

• Experimental use of neuropharmacologic drugs

• Transplant and artificial livers

Variceal Bleeding

• Devastating complication, prior to current

therapies, mortality was 30%

• Treatment: resuscitation, vasoconstrictors,

sclerotherapy, band ligation, TIPS, variceal

obliteration, surgical shunt

• Beta blockers as primary prophylaxis in

compensated cirrhosis with varices

• Dark towels and education

Ascites

• Portal hypertension leads to fluid retention

• Sodium retention leads to volume expansion

plus hypoalbuminemia which leads to low

oncotic pressure

• 2 year survival of cirrhosis with ascites is 50%

and decreases with diuretic resistant ascites

• Treatment:

Low sodium diet

Diuretics

Ascites

• Treatment if diuretic resistant (10%):

Transplant

Large volume paracentesis (8.4L/2weeks

+albumin 6-8g/L if following 2000mg

sodium diet with no urine sodium)

TIPS

Peritoneovenous shunt (rare)

Midodrine (increases renal perfusion)

TIPS

• Transjugular Intrahepatic Portosystemic

Shunt

• Hepatic encephalopathy occurs in ~ 30%

• Thrombosis and stenosis rates have

decreased with coated stents

• Contraindications: encephalopathy, alcoholic

hepatitis, MELD >18, advanced age, renal

disease

Spontaneous Bacterial Peritonitis

• Infection of preexisting ascitic fluid without

evidence of intra-abdominal source

• Signs/Symptoms: fever, abdominal pain,

tenderness, AMS, positive fluid culture

and/or elevated PMN leukocyte count

>250cells/mm3

• High mortality

• Treatment: prophylaxis in high risk, early

diagnostic paracentesis, IV antibiotics

Pruritus

• Interferes with quality of life including sleep

deprivation and depression

• Intrahepatic itch is associated with HBV,

HCV, cholestasis of pregnancy, PBC

• Extrahepatic itch is associated with

obstructive tumor and PSC

• Itch seems to be much higher in PBC

Pruritus

• Usually generalized, intermittent, starts in

palms/soles, and worse at night

• May lead to secondary lesions such as

excoriations, hyper/hypopigmentation,

lichenification, prurigo nodules, and scars

• Likely non-histaminergic pathway since most

chronic itch does not respond to

antihistamines

Pruritus

• May be related to hormones in females

• Consider endogenous opioids as source for

itching, because they cause degranulation of

cutaneous mast cells and activate mu

receptors

• No direct correlation between level of bile

salts etc. and itching

Pruritus• Treatments:

SSRIs (sertraline)

SNRIs (mirtazapine)

neuroleptics (gabapentin)

sedating antihistamines (hydroxyzine)

opioid antagonist (naltrexone)

UV light

behavioral therapy

bile acid resin (cholestyramine)

bile acid (ursodeoxycholic acid)

rifampicin

molecular adsorbent recirculating system

Hepatorenal Syndrome

• Development of acute renal failure in setting

of advanced liver disease

• Arterial splanchnic vasodilation leads

decreased renal perfusion leads to

decreased GFR

• Signs/Symptoms: oliguria, benign urine

sediment, very low urine sodium, rising

creatinine


• Type I: more serious, creatinine clearance

<20ml/min in 2 weeks or twofold increase in

creatinine to >2.5mg/dL, oliguria

• Type II: less severe, ascites resistant to

diuretics

• May occur in acute or chronic liver failure,

may be precipitated by acute insult, and is

least common in PBC


• Criteria:

Chronic or acute liver failure and portal hypertension

Creatinine >1.5mg/dL that progresses over days to weeks

Absence of other apparent cause

Urine red cell excretion <50 and protein excretion <500mg/day

Lack of improvement with volume expansion with albumin for at least 2 days and withdrawal of diuretics


• Treatment:

Vasopressin analogues + albumin can correct by causing constriction

Clonidine can raise GFR 25% by lowering renal sympathetic tone and vascular resistance, but benefit is not sustained

Midodrine + Somatostatin = vasoconstrictor + vasodilator inhibitor

Norepinephrine + Albumin = vasoconstrictor + protein replacement

TIPS and Dialysis and Transplant

Pulmonary

1. Hepatopulmonary Syndrome (20%):

• hepatic dysfunction + hypoxemia + intrapulmonary vascular dilations

• Type 1(improves with oxygen) and Type 2(true shunt)

• Etiology unknown, worsens cirrhosis prognosis

• Signs/Symptoms: cyanosis, clubbing, nail bed telangiectasias, orthodeoxia, platypnea, dyspnea, hypoxemia

• Treatment: transplant, medications give no benefit, TIPS (?), 5 year mortality is 20%

Pulmonary

2. Portopulmonary Hypertension (2-10%):

• cirrhosis leads to pulmonary artery hypertension

• Etiology unknown

• Signs/Symptoms: fatigue, edema, dyspnea, syncope, chest pain, JVD, increased P2 of the S2, TR, right heart failure

• Treatment: vasodilators (prostacyclin and sildenafil)

• Transplant contraindicated in most and only helps in very mild disease along with long term vasodilator therapy; 5 year mortality is 50-90%

Pulmonary

3. Hepatic Hydrothorax (10%):

• pleural effusion in cirrhosis without underlying cardiopulmonary disease resulting from ascites moving into pleural space (usually right side)

• Symptoms: dyspnea, cough, hypoxemia, chest discomfort

• Treatment: serial thoracenteses, fluid/sodium restriction, diuretics, draining catheters

Cardiovascular

“Cirrhotic Cardiomyopathy”:

• Increased cardiac output

• Increased contractility at rest

• Decreased systemic vascular resistance

• Systemic hypotension

• Blunted response to stress

Pain in Liver Disease

Pain

• Most pain medications are metabolized by

the liver

• Try to avoid complications including

encephalopathy, hepatorenal syndrome, and

bleeding

• Liver dysfunction = metabolism impairment

• Drug removal affected by hepatic blood flow,

enzyme capacity, and plasma protein binding

Pain

• Low serum protein or albumin can cause

increased levels of free drug if it is usually

protein bound

• Severe cholestasis can affect some drug

clearance

• Cirrhotic patients often have renal

impairment, which may require dose

adjustment of renal eliminated drugs

Pain

Acetaminophen:

• Doubled half-life

• In cirrhosis and no alcohol: maximum dose

2-3g/day for long term use

• In cirrhosis + alcohol: no long term studies,

but consensus is <2g/day

• 3-4g/day short term use still safe despite

FDA changes

Pain

NSAIDs:

• Increased serum levels due to liver metabolism and highly protein bound

• Renal impairment in cirrhosis due inhibition of prostaglandins leading to decreased renal perfusion, reduced GFR, and sodium retention

• Also cause increased bleeding in cirrhosis

• No studies for COX-2 inhibitors in cirrhosis

Pain

Opioids:

• No evidence based guidelines exist

• Mayo Clinic says opioids should be avoided

due to increased encephalopathy

• In cirrhosis, decreased clearance, increased

bioavailability, and prolonged half-life lead to

drug accumulation

• Careful monitoring for side effects required

Pain

Opioids:

• Opioids should be adjusted for GFR

• Morphine is poorly excreted in renal

insufficiency

• Hydromorphone and fentanyl seem to be the

least affected by renal dysfunction

• Fentanyl has less hemodynamic disturbance

due to lack of histamine release

Pain

Opioids:

• High hepatic extraction (first pass

metabolism): morphine and fentanyl have

higher bioavailability in cirrhotic patients

• Liver dysfunction = decreased clearance

• Liver disease does not impact methadone

bioavailability due to low hepatic extraction

Pain

Opioids:

• Metabolism of methadone, fentanyl, and

hydromorphone does not yield toxic

metabolites and may be better tolerated

• Methadone should be avoided with active

alcohol use because alcohol inhibits

metabolism of methadone

Pain

Others:

• Less potent TCAs should be used and started at

very low doses and beware of side effects

• Anticonvulsants should also be started at low

and less frequent doses

• Gabapentin is preferred because it is not

metabolized by the liver or protein bound, but it

is renally excreted (pregabalin is similar)

What Have We Learned?

• Common Causes of Liver Disease

• Hospice Criteria for Terminal Diagnosis of

Liver Disease

• Treatment of Symptoms of Liver Disease

ReferencesLocal Coverage Determination (LCD) for Hospice – Liver Disease (L31536); Palmetto GBA; effective 10.1.2011.

WWW.UpToDate.Com; 2011.

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Fregonese L and Stolk J: Hereditary Alpha-1-Antitrypsin Deficiency and its Clinical Consequences; Orphanet Journal of Rare Diseases 2008 3:16; 1-9.

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Huffmyer J and Nemergut E; Respiratory Dysfunction and Pulmonary Disease in Cirrhosis and Other Hepatic Disorders; Respiratory Care August 2007 Vol 52 No 8: 1030-1036.

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Butterworth R; Hepatic Encephalopathy – A Serious Complication of Alcoholic Liver Disease; Alcohol Research and Health; Vol. 27, No. 2, 2003; 143-145.

McHuthcinson J; Understanding Hepatitis C; The American Journal of Managed Care; Vol. 10. No. 2. supplement; S21-29.

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Fox E et al; Evaluation of Prognostic Criteria for Determining Hospice Eligibility in Patients with Advanced Lung, Heart, or Liver Disease; JAMA Nov 1999; Vol. 282, No. 17; 1638-1645.

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Merry

Christmas

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